1. Field of the Invention
The present invention relates generally to the fields of immunology and cancer biology. More particularly, it concerns modified peptide antigen compositions and methods of use therefor.
2. Description of Related Art
Immunotherapy refers to the technique of using a patient's immune system against tumor cells or infectious organisms. With respect to cancer, the objective is to direct the patient's immune system against tumor cells by targeting antigens (Ag) that are specific to or preferentially expressed by tumor cells. These antigens thus represent a potential target for methods and compositions of immunotherapy. However, some antigens are present either in low levels in normal cells or in fetal development. For example, oncofetal antigen is a carcinoembryonic antigen (CEA) which is expressed in fetal development and in most adenocarcinomas of entodermally-derived digestive system epithelia, as well as in breast tumor cells and non-small-cell lung cancer cells (Thomas et al., 1990).
As tumor antigen are self-antigen, they are recognized with low-affinity by both cytotoxic T lymphocytes-tumor infiltrating lymphocytes (CTL-TIL) and vaccination-induced CTL, because high avidity (hi-av) CTL are silenced. In addition to being weak immunogens, the effectors induced by antigen variants are often cross-reactive rather than specific for the tumor antigen. A second limitation of the antigen of the type used above is that the tumor antigen is presented in small amounts, in part due to the decreased levels of MHC-I expressed by the tumor compared with healthy tissue. Thus, although a number of approaches have been developed recently for tumor vaccination, these approaches have failed to show significant effects both on cure-rate, and immunological responses to vaccine treatment in patients. This poor immunogenicity requires novel methods to improve the immunogenicity of the tumor antigen.
Typically, the induction of tumor immunity by functional CTL requires: (1) expansion of “naive” or “stand-in” precursors of effector CTL (eCTL) to increase the pool of responders to tumor. This is because disease progression may expand tumor cells to very high numbers, thus only a large pool of CTL precursors can assure expansion of eCTL to similarly high numbers, without exhaustion due to end-stage proliferation and differentiation (2) generation of hi-av eCTL which recognize even small amounts of antigen on tumor; (3) protection of hi-av eCTL from deletion (elimination) at re stimulation with antigen and cytokines; and (4) induction of hi-av memory CTL (mCTL), from eCTL or activated CTL.
Recent advances provided partial answers to the first and second requirements by: (1) expanding precursors of CTL for model antigen using weak and null agonists; (2) identifying hi-av CTL in melanoma, although in small numbers. The other requirements, hi-av CTL protection from elimination and induction of mCTL, are still poorly understood. However, novel approaches are needed to induce, to protect from apoptosis, and to direct hi-av CTL to the memory pool, as shifting the response to low-affinity CTL or non-specific effectors occurs when enhancer antigen generated by sequence changes induce cross-reactive CTL.
Developing successful immunotherapies, including cancer therapies, thus imposes significant constraints for CTL induction, because of (a) the tolerance and anergy induced by inappropriate antigen stimulation plus type II cytokines; (b) the predominance of low-affinity CTL in the periphery: either escaped from tolerance, or induced by antigen and their agonists (an increase in the number of eCTL may not compensate for their low affinity for tumors); (c) the limited understanding of the relationship between the activation of TCR signaling, cytokine signaling and activation of survival pathways in mCTL; (d) costimulatory molecules,. cytokine receptors and death receptors are not clone specific; (e) induction of memory cells requires either weaker costimulation and/ or a slower rate of proliferation of activated CTL than that of effector CTL; and (f) survival effects are mediated by CD95 and Bcl-2 family pathways. Therefore, there is a need for novel methods and compositions for modulating a CTL response and for improved methods of immunotherapy.